The delivery of medications directly to specific parts of the body has several advantages over systemic administration. Lower doses of medication can be used with site specific administration and systemic toxicities of drug therapies can be mitigated. Furthermore, delivery port implantable devices are used regularly in the delivery of chemotherapy and medications to allow direct administration of certain medications best administered through direct access to the venous system, central nervous system and peritoneal cavity.
In some organs of the body, direct administration of certain drugs may be required to achieve therapeutic doses of medication without inducing serious toxicity. For example, the blood-brain barrier (BBB) protects the brain from potentially toxic substances, but also restricts the passage of most drug molecules. Because of the BBB, direct administration of drugs may be required to achieve therapeutic concentrations for the treatment of cancer, neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's Disease (PD), and other conditions.
Alternatively, devices for local, repeatable, and chronic drug delivery can be used. These devices contain catheters that distribute drug to specific tissues and may or may not contain a reservoir for storing drug. These devices include implantable drug pump systems, for example, Ommaya Rickham reservoirs and Port-A-Cath® devices. These devices deliver either a bolus or slow infusion of drugs to specific regions of the body. The types of drugs that can be used range from pain medications (e.g., morphine) to chemotherapeutics (e.g., methotrexate, cytarabine).
Cerebrospinal fluid (CSF) is a clear, colorless, body fluid found in the brain and spinal cord. CSF is produced in the choroid plexuses of the ventricles of the brain and absorbed in the arachnoid granulations. There is about 125 mL of CSF at any one time, and about 500 mL is generated every day. CSF acts, in part, as a cushion for the brain, providing basic mechanical and immunological protection to the brain inside the skull. The CSF also serves a vital function in cerebral autoregulation of cerebral blood flow. Chronic administration of small molecule medications to the brain CSF is unexplored especially medications with short half-lives. The only two molecules that have ever been looked at chronically are morphine and baclofen which have barely been explored but have been used because they already have been used in CSF administration in the spine. Baclofen's half-life is on the order of five hours and morphine's half-life is on the order of two hours.
Acute administration has been looked at primarily in the form of short term boluses and primarily for treatment of leptomeningeal disease. In fact, it has been decided that chronic administration of drugs into the CSF will not work for brain disease other than for leptomeningeal disease which is not within the brain itself
CSF flow is typically thought to go from the brain to one lateral ventricle, to the third ventricle and fourth and out over and under the brain convexities before being reabsorbed. In addition, animals have vastly different size and scale to their brains and they unexplored relative to other bodily organs and systems. The animals used in most testing of CSF flow is rats who have a 111000 the size of the human brain and even primates have a brain which is at best 1/10th the size of the human brain for large experimental primates. Furthermore, clinical results are expected to be different in human subjects than in animals. As a result of these and other factors allometric scaling is expected to be vastly off Allometric equations take the general form Y=aM h, where Y is some biological variable, M is a measure of body size, and b is some scaling exponent. In allometry, equations are often presented in logarithmic form so that a diverse range of body sizes can be plotted on a single graph.
It would be desirable, therefore, to determine a method, system, composition, and/or protocol resulting in the successful chronic administration of medications with short half-lives directly to the brain.